Nontypeable Haemophilus influenzae (NTHi) is an important cause of otitis media (OM) in children and respiratory tract diseases in adults (Klein, J. O. et al. 1992 Adv Pediatr 39:127-156; Murphy, T. F. et al. 1987 Rev Infect Dis 9:1-15; Musher, D. M. et al. 1983 Ann Intern Med 99:344-350). Moraxella (Branhamella) catarrhalis (Catlin, B. W. 1990 Clin Microbiol Rev 3:293-320; Doern, G. V. 1986 Diagn Microbiol Infect Dis 4:191-201; Enright, M. C., and H. McKenzie 1997 J Med Microbiol 46:360-371) is recognized as the third-most-common pathogen causing otitis media and sinusitis in children, after Streptococcus pneumoniae and nontypeable Haemophilus influenzae (Bluestone, C. D. 1986 Drugs 31(Suppl. 3): 132-141; Faden, H. et al. 1994 J Infect Dis 169:1312-1317). This gram-negative diplococcus is also a cause of respiratory tract infections in adults (Boyle, F. M. et al. 1991 Med J Aust 154:592-596; Sarubbi, F. A. et al. 1990 Am J Med 88:9S-14S), especially those with chronic obstructive pulmonary diseases (Nicotra, B. et al. 1986 Arch Intern Med 146:890-893) or compromised immune systems (Alaeus, A. and G. Stiemstedt Scand J Infect Dis 23:115-116; Enright, M. C. and H. McKenzie. 1997 J Med Microbiol 46:360-371).
Nontypeable Haemophilus influenzae (NTHi) is an important cause of otitis media in children and of pneumonitis in adults with depressed resistance. Lipooligosaccharide (LOS) is a major surface antigen of NTHi and elicits bactericidal and opsonic antibodies. Gu, X. X. et al. 1996 Infect Immun 64:4047-4053 prepared detoxified LOS (dLOS) protein conjugates from NTHi for use as experimental vaccines. LOS from NTHi 9274 was treated with anhydrous hydrazine and had its toxicity reduced to clinically acceptable levels. Hydrazine treatment of NTHi LOS resulted in a 10,000-fold reduction in the level of “endotoxin”, which is at clinically acceptable levels (W.H.O. Expert Committee on Biological Standardization 1991 W.H.O. Tech Rep Ser 814:15-37). dLOS was bound to tetanus toxoid (TT) or high-molecular-weight proteins (HMPs) from NTHi through a linker of adipic acid dihydrazide to form dLOS-TT or dLOS-HMP. The molar ratio of the dLOS to protein carriers ranged from 26:1 to 50:1. The antigenicity of the conjugates was similar to that of the LOS alone as determined by double immunodiffusion. Subcutaneous or intramuscular injection of the conjugates elicited a 28- to 486-fold rise in the level of immunoglobulin G antibodies in mice to the homologous LOS after two or three injections and a 169- to 243-fold rise in the level of immunoglobulin G antibodies in rabbits after two injections. The immunogenicity of the conjugates in mice and rabbits was enhanced by formulation with monophosphoryl lipid A plus trehalose dimycolate. In rabbits, conjugate-induced LOS antibodies induced complement-mediated bactericidal activity against the homologous strain 9274 and prototype strain 3189. These results indicate that a detoxified LOS-protein conjugate is a candidate vaccine for otitis media and pneumonitis caused by NTHi. Gu, X. X. et al. 1997 Infect Immun 65:4488-4493 determined that subcutaneous or intramuscular injections of detoxified-lipooligosaccharide (dLOS)-protein conjugates from NTHi protected against otitis media in chinchillas.
Moraxella (Branhamella) catarrhalis (M. catarrhalis) is an important cause of otitis media and sinusitis in children and of lower respiratory tract infections in adults. Lipooligosaccharide (LOS) is a major surface antigen of the bacterium and elicits bactericidal antibodies. Treatment of the LOS from strain ATCC 25238 with anhydrous hydrazine reduced its toxicity 20,000-fold, as assayed in the Limulus amebocyte lysate (LAL) test. The detoxified LOS (dLOS) was coupled to tetanus toxoid (TT) or high-molecular-weight proteins (HMP) from nontypeable Haemophilus influenzae through a linker of adipic acid dihydrazide to form dLOS-TT or dLOS-HMP. The molar ratios of dLOS to TT and HMP conjugates were 19:1 and 31:1, respectively. The antigenicity of the two conjugates was similar to that of the LOS, as determined by double immunodiffusion. Subcutaneous or intramuscular injection of both conjugates elicited a 50- to 100-fold rise in the geometric mean of immunoglobulin G (IgG) to the homologous LOS in mice after three injections and a 350- to 700-fold rise of anti-LOS IgG in rabbits after two injections. The immunogenicity of the conjugate was enhanced by formulation with monophosphoryl lipid A plus trehalose dimycolate. In rabbits, conjugate-induced antisera had complement-mediated bactericidal activity against the homologous strain and heterologous strains of M. catarrhalis. These results indicate that a detoxified LOS-protein conjugate is a candidate for immunization against M. catarrhalis diseases.
Current pediatric immunization programs include too many injections in the first months of life. Oral or nasal vaccine delivery eliminates the requirement for needles. There is a need for mucosal vaccines against NTHi- and M. catarrhalis-caused otitis media in children and other NTHi- and M. catarrhalis-caused diseases in children and adults.